ProjectSummary Inwomen,menopausesignificantlyincreasestheriskforstrokeandheartdisease.Usingacyclicmiddle-aged femaleratstomodeltheestrogen-deficientpostmenopausalstate,wefoundthatischemicstrokeproduced largerbraininfarctsinthispopulationascomparedtonormallycyclingadultfemales.Furthermore,while estrogentreatmentisprotectivetoyoungfemales,hormonetreatmentparadoxicallyincreasedtissuedamage inolderacyclicfemales.ThesedataarecongruentwiththeWomen?sHealthInitiative(WHI)study,wherethe riskforstrokewaselevatedinolderwomenreceivinghormonetherapy,andunderscorestheneedfornovel therapeuticapproachesforthisgroup. Webegantoaddresstheneedforeffectivestroketherapiesinanolderfemalepopulationduringtheprevious fundingperiodandreportedthatInsulinlikegrowthfactor(IGF)-1reversestheneurotoxiceffectsofestrogen onstrokewhengiventoestrogen-treatedmiddle-agedfemales.Furthermore,IGF-1alsoimprovesstroke outcomeswhengiventoestrogen-deficient,acyclicmiddle-agedfemalerats.Extrapolatedtotheclinical setting,thesefindingsraisetheexcitingpossibilitythatacute,post-ischemicIGF-1treatmentcouldalleviate stroke-inducedneuronallossinolderwomenwhoarenon-usersorcurrentusersofhormonetherapy.To exploitthetranslationalpotentialofthislineofresearch,thisrenewalapplicationwillfocusonanovel mechanismofactionforIGF-1and,moreimportantly,testtheabilityofthishormoneandmicroRNAsthat regulateIGF-1pathwaystoimprovebothshort-andlong-termstrokeoutcomes. Inthisproposal,wewillusenovelexperimentalapproachestotestthehypothesisthatIGF-1treatmentafter strokereducesischemia-inducedhyper-permeabilityofthebloodbrainbarrier(BBB)bystabilizingthe morphologyofendothelialcells(SpecificAim1);?thatastrocyte-derivedIGF-1maintainsBBBintegrityafter stroke(SpecificAim2),andfinally,todeterminewhetherIGF-1-mediatedneuroprotectionintheacutephaseof strokepreservesstriatalinputsfrommidbraindopaminergicneuronsthatmediatemotorfunctionandaffective behaviors(SpecificAim3). IntheaftermathoftheWHIstudy,thereisasignificantandpressingneedtofindnewwaystoprotectolder, post-menopausalwomenfromdisabilityduetoischemicstroke.Collectivelythesestudieswillidentifycellular targets,suchasastrocytes,thatincreasestrokesusceptibilityinagingpopulations,withthegoalofdeploying hormonalandepigenetictherapieswithsurgicalprecision.Thesestudiesarethereforeexpectedtoformthe foundationforstroketherapytailoredtoolderwomen.